Process for preparing 2-[bis(aryl)methyl]benzoic acids

ABSTRACT

Process comprises the combination of the two steps of condensing Y-benzaldehyde with N-R 2  -N-R 3  -aniline and 3-N-R-N-R 1  -benzoic acid, under acidic conditions to produce 2-[(Y-phenyl) (4-N-R 2  -N-R 3  -aminophenyl)methyl]-5-N-R-N-R 1  -aminobenzoic acid, and oxidizing said benzoic acid to produce 3-(Y-phenyl)-3-(4-N-R 2  -N-R 3  -aminophenyl)-6-N-R-N-R 1  -aminophthalide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 328,918, filedDec. 9, 1981, now U.S. Pat. No. 4,399,291.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to a novel two-step process for the preparationof 3,3-bis(phenyl)phthalides useful in the art of carbonless duplicatingas, for example, in pressure-sensitive systems and in thermal markingsystems and to a novel process for the preparation of2-[bis(phenyl)methyl]benzoic acid intermediates to said phthalides.

(b) Description of the Prior Art

It is well established in the dyestuff art that benzaldehyde condenseswith two equivalents of aniline in the presence of an acidic material,for example, sulfuric acid to form diaminotriphenylmethane. Similarly,the condensation of p-aminobenzaldehyde with two equivalents of anilineyields leuco Pararosaniline, 4,4',4"-triaminophenylmethane. And in ananalgous reaction leuco crystal violet,4,4',4"-tris(dimethylaminophenyl)methane is obtained from theinteraction of p-dimethylaminobenzaldehyde with two equivalents ofN,N-dimethylaniline in the presence of an acidic material. On the otherhand, the chemical moiety known as3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide, commonly knownas Crystal Violet Lactone or simply CVL is prepared by a number ofsynthetic routes. One such route is the multi-step synthesis in whichMichler's hydrol, 4,4'-dimethylaminobenzhydrol, is reacted with3-dimethylaminobenzoic acid in the presence of sulfuric acid to obtain2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid whichis isolated. Then said isolated benzoic acid is oxidized in a secondstep to obtain the phthalide known as CVL. However, the Michler's hydrolused as an intermediate in the process for preparing CVL is itself,prepared by a two-step synthesis. In the first step, two equivalents ofN,N-dimethylaniline and formaldehyde are interacted to obtain Michler'smethane which is isolated. In the second step, Michler's methane isoxidized with lead dioxide to obtain Michler's hydrol.

In a second synthetic route to CVL, which is also a multi-stepsynthesis, 4-dimethylaminobenzaldehyde is reacted with3-dimethylaminobenzoic acid to obtain3-(4-dimethylaminophenyl)-6-dimethylaminophthalide in the first step. Ina second step, the 3-(4-dimethylaminophenyl)-6-dimethylaminophthalidefrom step one is interacted with N,N-dimethylaniline in the presence ofa Friedel-Crafts type catalyst to obtain2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. In athird step, the benzoic acid from step two is oxidized to obtain3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide.

In another known process for the preparation of CVL there are threesteps. The first step comprises the interaction of the methyl ester of2-formyl-5-dimethylaminobenzoic acid with two equivalents ofN,N-dimethylaniline to obtain the methyl ester of2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. Afterisolation, this benzoic acid is oxidized in the second step and finallyin the third step the oxidized product is saponified and the lactonering is closed to obtain the3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide (CVL).

In all of these art-known processes there are a multiple of syntheticsteps required usually with isolation of the intermediate material aftereach of the steps. In addition, many of the starting materials requiredfor these processes themselves have to be made by processes involvingone or more synthetic steps. Each step required increases the cost ofthe final desired product, uses additional valued raw materials andincreases the disposal problems of both the liquid and solid wastes fromthe overall synthetic processes.

The following items to date appear to constitute the most relevant priorart with regard to the instant invention.

U.S. Pat. No. 2,417,897 and its corresponding U.S. Pat. No. Re. 23,024,which issued Mar. 25, 1947 and Aug. 17, 1948, respectively, disclose athree-step process for the preparation of3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide, Crystal VioletLactone (CVL). In the first step, 3-dimethylaminobenzoic acid isprepared from 3-aminobenzoic acid by alkylating the free amine usingmethyl iodide in the presence of potassium hydroxide. In the secondstep, the 3-dimethylaminobenzoic acid is condensed with4,4'-bis(dimethylamino)benzhydrol in the presence of sulfuric acid toobtain 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid.In the third step, the2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid isoxidized using lead dioxide in dilute hydrochloric acid to obtain theCVL.

U.S. Pat. No. 4,045,458, which issued Aug. 30, 1977 discloses a processfor the preparation of2-[bis(4-dialkylaminophenyl)methyl]-5-dialkylaminobenzoic acids bycondensing a 3-(4-dialkylaminophenyl)-6-dialkylaminophthalide with anN,N-dialkylaniline in the presence of a Friedel-Crafts type catalyst.The patent further discloses a process in which the2-[bis(4-dialkylaminophenyl)methyl]-5-dialkylaminobenzoic acid obtainedin the above process can be oxidized utilizing various oxidizing agentsto obtain 3,3-bis(4-dialkylaminophenyl)-6-dialkylaminophthalides.

In the fourth Edition of Beilsteins Handbuch der Organische Chemie, Vol.14, page 549, 4,4"-bis-dimethylaminotriphenylmethanecarbonsaure-(2) isreported as a by-product in the preparation of3-(4-dimethylaminophenyl)phthalide by the condensation ofdimethylaniline with o-phthalaldehydic acid in the presence of acatalyst such as zinc chloride, phosphorous oxychloride or potassiumbisulfate.

U.S. Pat. No. 3,971,821, issued July 27, 1976, discloses a three-stepprocess for the preparation of3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide which comprisesin the first step reacting the methyl ester of2-formyl-5-dimethylaminobenzoic acid with two molecular equivalents ofN,N-dimethylaniline to obtain the methyl ester of2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid whichin turn is oxidized in a second step and the oxidized product issaponified in the third step to obtain the3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide (CVL).

U.S. Pat. No. 3,995,088, issued Nov. 30, 1976, discloses a process forthe preparation of leuco methylene dyestuffs which involves the reactionof two molecular equivalents of a substituted N,N-dialkylaniline withone molecular equivalent of a benzaldehyde in the presence of an acidicsubstance and optionally having urea present during the reaction.

(c) Patent Activities of Others

British Patent Publication No. 2,072,163, which was published Sept. 30,1981, teaches a process for the preparation of2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid byinteracting 4-dimethylaminobenzaldehyde, urea and N,N-dimethylaniline inhydrochloric acid. The reaction mass is then made alkaline and theexcess N,N-dimethylaniline is steam distilled from the mixture and aftercooling 1,3-bis(4',4"-dimethylaminodiphenyl-methyl)urea is obtained. Theurea derivative is then reacted with 3-dimethylaminobenzoic acid indilute sulfuric acid and after rendering the reaction mixture alkaline,2-[4,4'-bis(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid (LeucoCrystal Violet Lactone) is isolated. This reference appeared subsequentto applicants' invention described herein and less than one year priorto the filing date of this application.

SUMMARY OF THE INVENTION

In one of its process aspects, the invention relates to a two-stepprocess for producing 3,3-bis(phenyl)substituted-phthalides whichcomprises interacting in the first step an aniline, a benzaldehyde and abenzoic acid to obtain 2-[bis(phenyl)methyl]benzoic acids which areoxidized in the second step to obtain the corresponding phthalides.

In a second of its process aspects, the invention relates to a processfor producing 2-[bis(phenyl)methyl]benzoic acids which comprisesinteracting an aniline, a benzaldehyde and a benzoic acid to obtain said2-[bis(phenyl)methyl]-substituted benzoic acids.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically, this invention in one of its process aspects residesin the novel process for the preparation of 3-(Y-phenyl)-3-(4-N-R² -N-R³-aminophenyl)-6-N-R-N-R¹ -aminophthalides, which are particularly usefulas colorless precursors in the art of carbonless duplicating and thermalmarking, and which are of the formula ##STR1## wherein R, R¹, R² and R³may be identical or different and each represents hydrogen, non-tertiaryalkyl of one to four carbon atoms, hydroxyalkyl of two or three carbonatoms, phenyl, benzyl or phenyl or benzyl substituted in the benzenering by one or two of halo or alkyl of one to three carbon atoms; and Yrepresents hydrogen, halo, non-tertiary alkyl of one to four carbonatoms, non-tertiary alkoxy of one to four carbon atoms, or dialkylaminoor N-alkylbenzylamino in which alkyl is non-tertiary alkyl of one tofour carbon atoms and benzyl may be substituted in the benzene ring byone or two of halo or alkyl of one to three carbon atoms which comprisesin a first step, reacting in approximately equimolecular proportions aY-benzaldehyde, an N-R² -N-R³ -aniline and a 3-(N-R-N-R¹)aminobenzoicacid in which R, R¹, R², R³ and Y each have the same respective meaningsgiven for Formula I, in an acidic medium to produce a2-[(Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoicacid of the formula ##STR2## and in a second step, oxidizing said2-[(Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R1-aminobenzoicacid of Formula II in an aqueous alkaline medium to produce a3-(Y-phenyl)-3-(4-N-R² -N-R³ -aminophenyl)-6-N-R-N-R¹ -aminophthalide ofFormula I.

In a first particular embodiment in accordance with its first processaspect, the invention sought to be patented resides in the novel processfor preparing a 3-(4-Y-phenyl)-3-(4-N-R² -N-R³ -aminophenyl)-6-N-R-N-R¹-aminophthalide of Formula I. Particularly preferred within thisembodiment is the process for preparing a phthalide of Formula I whereinY is dialkylamino or N-alkylbenzylamino in which alkyl is non-tertiaryalkyl of one to four carbon atoms.

In a second particular embodiment in accordance with its first processaspect, the invention sought to be patented resides in the novel processfor preparing a 3-(Y-phenyl)-3-(4-N-R² -N-R³ -aminophenyl)-6-N-R-N-R¹-aminophthalide of Formula I wherein the acidic medium employed in thefirst step is selected from the group consisting of aqueous sulfuricacid, hydrochloric acid and methanesulfonic acid.

In a third particular embodiment in accordance with its first processaspect, the invention sought to be patented resides in the novel processfor preparing a 3-(Y-phenyl)-3-(4-N-R² -N-R³ -aminophenyl)-6-N-R-N-R¹-aminophthalide of Formula I wherein urea is present in the acidicmedium of the first step.

This invention, in its second process aspect, resides in the process forpreparing 2-[(Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹-aminobenzoic acid of the formula ##STR3## wherein R, R¹, R² and R³ maybe identical or different and each represents hydrogen, non-tertiaryalkyl of one to four carbon atoms, hydroxyalkyl of two or three carbonatoms, phenyl or benzyl or phenyl or benzyl substituted in the benzenering by one or two of halo or alkyl of one to three carbon atoms; and Yrepresents hydrogen, halo, non-tertiary alkyl of one to four carbonatoms, non-tertiary alkoxy of one to four carbon atoms, or dialkylaminoor N-alkylbenzylamino in which alkyl is non-tertiary alkyl of one tofour carbon atoms and benzyl may be substituted in the benzene ring byone or two of halo or alkyl of one to three carbon atoms which comprisesreacting in approximately equimolecular proportions a Y-benzaldehyde, anN-R² -N-R³ -aniline and a 3-N-R-N-R¹ -aminobenzoic acid in which R, R¹,R², R³ and Y each have the meanings given for Formula II, in an acidicmedium.

In a first particular embodiment in accordance with its second processaspect, the invention sought to be patented resides in the novel processfor preparing a 2-[(4-Y-phenyl)(4-N-R² -N-R³-aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acid of Formula II.Particularly preferred within this embodiment is the process forpreparing a 2-[(4-Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹-aminobenzoic acid of Formula II wherein Y is a dialkylamino orN-alkylbenzylamino in which alkyl is a non-tertiary alkyl of one to fourcarbon atoms.

In a second particular embodiment in accordance with its second processaspect, the invention sought to be patented resides in the novel processfor preparing a 2-[(Y-phenyl)(4-N-R² -N-R³-aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acid of Formula II whereinthe acidic medium is selected from the group consisting of aqueoussulfuric acid, hydrochloric acid and methanesulfonic acid.

In a third particular embodiment in accordance with its second processaspect, the invention sought to be patented resides in the novel processfor preparing a 2-[(Y-phenyl)(4-N-R² -N-R³-aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acid of Formula II whereinurea is present in the acidic medium.

As used herein the term "halo" includes chloro, fluoro, bromo and iodo.Chloro is the preferred halo substituent because of the relatively lowcost and ease of preparation of the required chloro-substitutedintermediates and because the other halogens offer no particularadvantages over chloro. However, the other above-named halo substituentsare also suitable for practicing the processes of this invention.

The term "dialkylamino in which alkyl is non-tertiary alkyl of one tofour carbon atoms" denotes saturated, acyclic groups which may bestraight or branched as exemplified by dimethylamino, diethylamino,ethylmethylamino, dipropylamino, dibutylamino, isobutylmethylamino andthe like.

The term "N-alkylbenzylamino in which alkyl is non-tertiary alkyl of oneto four carbon atoms and benzyl may be substituted in the benzene ringby one or two of halo or alkyl of one to three carbon atoms" denotes anamino moiety which is substituted with an acyclic group which may bestraight or branched and one benzyl group as exemplified byN-methylbenzylamino, N-ethylbenzylamino, N-propylbenzylamino,N-sec-butylbenzylamino, N-ethyl(2,5-dimethylbenzyl)amino,N-ethyl(4-chlorobenzyl)amino and the like.

As used herein the terms "alkyl of one to three carbon atoms" and"non-tertiary alkyl of one to four carbon atoms" denote saturatedmonovalent straight or branched aliphatic hydrocarbon radicals includingmethyl, ethyl, propyl, isopropyl, butyl and isobutyl.

The term "non-tertiary alkoxy of one to four carbon atoms" includesaturated acyclic, straight or branched-chained groups such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and isobutoxy.

As used herein the term "hydroxyalkyl of two or three carbon atoms"denotes saturated monovalent straight or branched aliphatic hydrocarbonradicals containing a terminal hydroxy substituent includinghydroxyethyl, hydroxypropyl, hydroxyisopropyl and the like.

As used herein the term "acidic medium" denotes any aqueous acidicmedium capable of dispersing, partially dissolving or completelydissolving the reactants thus providing a fluid medium for thesereactants to interact forming the desired 2-[bis(phenyl)methyl]benzoicacids. Examples of the acids which may be utilized in the aqueous acidicmedium are sulfuric acid, hydrochloric acid, methanesulfonic acid,phosphorous acid, hydrobromic acid, acetic acid, chloroacetic acid,dichloroacetic acid and so forth.

The processes of this invention afford a novel convenient andeconomically advantageous synthetic route to a large number of knowncompounds which are 3,3-bis(phenyl)-6-N-R-N-R¹ -aminophthalides of thetype represented by Formula I. Many species defined by Formula I arewell-known in the prior art as being useful as colorless precursors incarbonless duplicating systems, for example,3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide or, as thiscompound has been more simply designated, Crystal Violet Lactone (CVL).

The processes of this invention also afford2-[bis(phenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acids of the typerepresented by Formula II. The 2-[bis(phenyl)methyl]-5-N-R-N-R¹-aminobenzoic acids of Formula II are primarily useful as intermediatesto the phthalides depicted by Formula I. Moreover, the2-[bis(phenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acids of Formula II arealso useful as color precursors in pressure-sensitive carbonlessduplicating systems and in thermal marking systems. They develop coloron contact with the acidic clay and phenolic resin developing sheetscommonly used in carbonless systems at a much slower rate than do thephthalides of Formula I.

The novel compounds represented by Formulas I and II above areessentially colorless in the depicted form. When the compounds ofFormulas I and II are contacted with an acidic medium for example,silica gel or one of the types regularly employed in pressure-sensitivecarbonless duplicating systems, for example, silton clay or phenolicresins, they develop a colored image of good to excellent tinctorialstrength. The development of color on contact with silica gel, siltonclay or a phenolic resin demonstrates that these compounds are highlysuitable for use as colorless precursors, that is, color-formingsubstances in pressure-sensitive carbonless duplicating systems. Forsuch application, the compounds may be incorporated in any of thecommercially-accepted systems known in the carbonless duplicating art. Atypical technique for such application is as follows. Solutions of thecolorless precursor compounds in suitable aromatic solvents aremicroencapsulated by well-known procedures. The microcapsules are coatedon the reverse side of a transfer sheet with the aid of a suitablebinder and the coated transfer sheet is then assembled in a manifoldwith the microcapsule coated side in contact with a receiving sheetcoated with an electron accepting substance, for example, silton clay ora phenolic resin. Application of pressure to the manifold such as thatexerted by a stylus, typewriter or other form of writing or printingcauses the capsules on the reverse side to rupture. The solution of thecolor former released from the ruptured microcapsules flows to thereceiving sheet and on contact with the acidic medium thereon forms ablue to reddish-purple-colored image of good tinctorial strength. It is,of course, obvious that variants of this mode of application can beutilized. For example, the receiving sheet in a manifold canalternatively be coated with the subject compounds and the acidicdeveloping agent can be contained in microcapsules applied to thereverse side of the top sheet in the manifold.

It has also been found that when the compounds of Formulas I and II areintimately mixed with an acidic developer of the type generally employedin thermal papers, that is, papers which produce a colored image whencontacted with a heated stylus or heated type, for example, bisphenol A,heating of the mixture produces a colored image of varying shades fromblue to purple depending on the particular compound of the inventionemployed. The ability of the compounds of Formulas I and II to form adeep color when heated in admixture with an acidic developer such asbisphenol A, makes them useful in thermal paper marking systems, eitherwhere an original or a duplicate copy is prepared by contacting thethermal paper with a heated stylus or heated type in any of the methodsgenerally known in the art.

It has been found that the novel process of this invention produces2-[(Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoicacids by interacting a Y-benzaldehyde, an N-R² -N-R³ -aniline and a3-N-R-N-R¹ -aminobenzoic acid in the presence of an acidic material.This is surprising in view of the well established fact in the art ofdyestuff chemistry that a benzaldehyde will react with two equivalentsof an aniline, substituted or unsubstituted, to obtain the correspondingtriphenyl methane. Furthermore, in view of the known increasedreactivity of anilines compared to disubstituted-aminobenzoic acids,which is in keeping with the theory of relative reactivity as taught inbasic organic chemistry, it would be expected that the reaction of amixture consisting of a benzaldehyde, an N-R² -N-R³ -aniline and a3-N-R-N-R¹ -aminobenzoic acid would result predominantly in a[(Y-phenyl)-bis(N-R² -N-R³ -aminophenyl)]methane and a recovery of the3-N-R-N-R¹ -aminobenzoic acid. However, it has been found quiteunexpectedly that the major product formed by the process of thisinvention, which comprises interacting a Y-benzaldehyde, an N-R² -N-R³-aniline and a 3-N-R-N-R¹ -aminobenzoic acid in admixture in thepresence of an acidic material, optionally in the presence of urea, is a2-[(Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoicacid with a lesser amount of [(Y-phenyl)-bis(4-N-R² -N-R³-aminophenyl)]methane formed as a by-product.

The process of the instant invention for the preparation of the3-(Y-phenyl)-3-(4-N-R² -N-R³ -aminophenyl)-6-N-R-N-R¹ -aminophthalideshas advantages over the previously known processes for the preparationof these compounds. One advantage of this process is that there arefewer steps involved in the overall synthesis. This contributes to fewerby-products, and also to less solid and liquid waste to be disposed ofper unit of desired product. Also with fewer steps involved, the overallsynthesis effects an economic production savings per unit of product.Still another advantage over some of the earlier processes is that theinstant process obviates the use of heavy metal dioxides, for example,lead dioxide in the oxidation step for conversion of the benzoic acidintermediates to the final phthalide products and in preceedingintermediate steps. Thus the health hazards associated with the use ofheavy metals are eliminated by the instant process.

The best mode contemplated by the inventors of carrying out thisinvention will now be described so as to enable any person skilled inthe art to which it pertains to make and use the same.

In accordance with the first of the aforementioned process aspects ofthis invention, the 3-(Y-phenyl)-3-(4-N-R² -N-R³-aminophenyl)-6-N-R-N-R¹ -aminophthalides of Formula I are obtained byreacting in the first step approximately equimolar amounts ofY-benzaldehyde, an N-R² -N-R³ -aniline and a 3-N-R-N-R¹ -aminobenzoicacid wherein R, R¹, R², R³ and Y have the same respective meanings givenabove in Formula I. This reaction is conveniently carried out in anaqueous acidic medium, for example, dilute sulfuric acid, hydrochloricacid or methanesulfonic acid at a temperature in the range of 50° C. tothe reflux temperature of the reaction mixture for approximately onehour to approximately thirty hours. The 2-[(Y-phenyl)(4-N-R² -N-R³-aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acids of Formula II can beisolated by first diluting the reaction mixture with water, secondlyadding a sufficient amount of alkali, for example, sodium hydroxide,potassium hydroxide or ammonium hydroxide to render the mixture alkalineto a pH in the range of 10.0 to 14.0, and finally adjusting the pH to3.0 to 5.0 by the addition of an acid, for example, acetic acid,hydrochloric acid or sulfuric acid. The benzoic acids of Formula II canbe isolated by filtration or by decantation of the supernatant liquor.The isolated benzoic acids can be purified by conventional means such astrituration, recrystallization or reslurrying with a suitable organicliquid or by dissolving in a suitable alkali and reprecipitating byadding the alkaline solution to a dilute acid solution. Alternatively,the reaction mixture can be rendered alkaline and employed directly inthe oxidation step without isolation of the 2-[(Y-phenyl)(4-N-R² -N-R³-aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acids.

Although the reaction can be simply carried out in the acidic medium asdescribed above, the addition of urea has been found to provide adistinct advantage over the reaction carried out in the acid mediumalone. It has been found that better results are achieved when urea ispresent. The urea has the effect of increasing the yield of the desiredproduct and accelerating the reaction time. While it is not necessary torun the reaction in the presence of urea, it does provide the advantagesdescribed above.

The 3-(Y-phenyl)-3-(4-N-R² -N-R³ -aminophenyl)-6-N-R-N-R¹-aminophthalides of Formula I are obtained by oxidizing the appropriate2-[(Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R¹ -N-R²-aminobenzoic acids of Formula II. The oxidation is conveniently carriedout in aqueous alkaline solutions, for example, potassium hydroxide orsodium hydroxide, at a temperature in the range of 10° to 50° C. Theoxidizing agent can be a chemical oxidizing agent, for example,potassium persulfate, potassium permaganate or hydrogen peroxide.Alternatively, the oxidizing agent can be molecular oxygen either in theform of gaseous oxygen or air. The 3-(Y-phenyl)-3-(4-N-R² -N-R³-aminophenyl)-6-N-R-N-R¹ -aminophthalide thus produced is separated byfiltration or decantation by conventional means. The isolated phthalidecan be purified by conventional means such as trituration,recrystallization or reslurrying with a suitable organic liquid.

The Y-benzaldehydes required as starting materials in the preparation ofthe phthalides of Formula I and the benzoic acids of Formula II form anold and well-known class of compounds readily obtained by conventionalprocesses well-known in the art. The following list of compoundsexemplifies Y-benzaldehydes which are useful in the practice of theprocesses of this invention: benzaldehyde, 2-methylbenzaldehyde,2-chlorobenzaldehyde, 2-methoxybenzaldeyde, 3-methoxybenzaldehyde,4-methoxybenzaldehyde, 2-bromobenzaldehyde, 2-ethoxybenzaldehyde,3-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 2-fluorobenzaldehyde,4-isopropylbenzaldehyde, 4-dimethylaminobenzaldehyde,4-diethylaminobenzaldehyde, 4-di(n-propyl)aminobenzaldehyde,4-di(isopropyl)aminobenzaldehyde, 4-di(n-butyl)aminobenzaldehyde,4-di(sec-butylaminobenzaldehyde, 4-benzylaminobenzaldehyde,4-dibenzylaminobenzaldehyde, and 4-(N-ethylbenzylamino)benzaldehyde.

The N-R² -N-R³ -anilines of required as starting materials in thepreparation of the pthalides of Formula I and the benzoic acids ofFormula II constitute a well-known class of compounds many of which arecommercially available or readily obtained by conventional syntheseswell-known in the art. The following list of compounds exemplifies N-R²-N-R³ -anilines which are useful in the practice of the processes ofthis invention: N,N-dimethylaniline, N,N-diethylaniline,N,N-di(n-propyl)aniline, N,N-di(isopropyl)aniline,N,N-di(n-butyl)aniline, N,N-di(sec-butyl)aniline,N,N-di(isobutyl)aniline, N-benzyl-N-ethylaniline,N-ethyl-N-methylaniline, N-benzyl-N-methylaniline,N-benzyl-N-n-propylaniline, N-benzyl-N-sec-butylaniline,N-isopropyl-N-methylaniline, N-n-propyl-N-ethylaniline,N,N-dibenzylaniline, N-phenyl-N-methylaniline,N-(4-methylbenzyl)-N-methylaniline, N-(4-chlorobenzyl)-N-ethylaniline,N-(2,4-dichlorobenzyl)-N-methylaniline, andN-(4-methylphenyl)-N-ethylaniline.

The 3-N-R-N-R¹ -aminobenzoic acids required as starting materials in thepreparation of the phthalides of Formula I and the benzoic acids ofFormula II belong to a well-known class of compounds and are generallycommercially available or readily obtained by conventional means fromreadily available starting materials. The following compounds areexemplary of 3-N-R-N-R¹ -aminobenzoic acids useful in the processes ofthis invention: 3-aminobenzoic acid, 3-dimethylaminobenzoic acid,3-methylaminobenzoic acid, 3-(N-methyl-N-ethylamino)benzoic acid,3-(N-ethyl-N-butylamino)benzoic acid, 3-diethylaminobenzoic acid,3-(N-ethylbenzylamino)benzoic acid, 3-dibenzylaminobenzoic acid,3-ethylaminobenzoic acid, 3-[N-butyl-N-(4-chlorobenzyl)amino]benzoicacid, and 3-[N-methyl-N-(4-methylbenzyl)amino]benzoic acid.

The compounds prepared by the processes of this invention form a part ofa large and well known class of compounds and have known melting points.In addition, their infrared and nuclear magnetic resonance spectral dataare well established and they are readily identifiable in thin-layerchromatographic analysis (TLC). The molecular structures of thecompounds made by the processes of this invention were assigned on thebasis of the study of their infrared and nuclear magnetic resonancespectra in conjunction with the spectra of compounds prepared by the artdescribed methods and from the results of TLC analysis.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are uncorrected.

EXAMPLE 1

With stirring, a mixture of 15.3 g (0.1 mole) of 97.7 percent4-dimethylaminobenzaldehyde, 6.0 g (0.1 mole) of urea, 24.1 g (0.1 mole)of 98.8 percent N-ethyl-N-benzylaniline, 18.2 g (0.106 mole) of 96.2percent 3-dimethylaminobenzoic acid, 76.0 ml of water and 14.6 ml ofconcentrated sulfuric acid was maintained at a temperature in the rangeof 90° to 95° C. for approximately four and one-half hours. Slowly,200.0 ml of tap water was added to the reaction mixture and theresulting mixture was cooled to ambient temperature. A solution of 43.0g of 90 percent potassium hydroxide dissolved in 200.0 ml of water wasadded dropwise to the mixture. The resulting milky green mixture wasadjusted to pH 11.4 with the addition of a small amount of glacialacetic acid and filtered. No solid was collected. The filtrate wasadjusted to pH 4.6 by the gradual addition of glacial acetic acid. Thesolid which formed was collected by filtration and dried in a vacuumoven at approximately 46° C. The solid melted in the oven but solidifiedupon cooling to room temperature to obtain 48.0 g of ablue-green-colored solid which melted at 59° to 64° C. A small portionof this solid was dissolved in hot dilute sodium hydroxide. The solutionwas cooled to ambient temperature and made acid by the gradual additionof glacial acetic acid. The solid which precipitated was collected byfiltration, washed with water and dried in vacuo. The resulting paleblue-colored solid melted at 64° to 67° C. The nuclear magneticresonance spectrum of this solid confirmed that approximately 80 percentof the solid had a chemical structure consistent with the compound2-[(4-dimethylaminophenyl)(4-N-ethyl-N-benzylaminophenyl)methyl]-5-dimethylaminobenzoicacid (Formula II: Y═4--N(CH₃)₂ ; R═R¹ ═CH₃ ; R² ═C₂ H₅ ; R³ ═CH₂ C₆ H₅).A significant infrared maximum appeared at 1610 (C═O;s) cm⁻¹.

EXAMPLE 2

A mixture of 46.0 ml of water, 49.4 g of 70 percent methanesulfonicacid, 14.9 g (0.1 mole) of 4-dimethylaminobenzaldehyde, 16.5 g (0.1mole) of 3-dimethylaminobenzoic acid and 12.1 g (0.1 mole) ofN,N-dimethylaniline was maintained at reflux temperature with stirringfor approximately twenty-four hours. After cooling, the resultingsolution was added slowly with stirring to a mixture of 700.0 ml ofwater and 27.0 ml of 50 percent aqueous sodium hydroxide. The resultingsolution having a pH of 12.6 was maintained at 60° C. for approximatelyone hour. Two grams of diatomateous earth was added to the solution andthe resulting mixture was clarified by filtration. The hot filtrate wasadded slowly with stirring to a solution of 100.0 ml of water and 10.0ml of glacial acetic acid. Glacial acetic acid was added slowly toadjust the pH to 4.9 and stirring was continued for approximatelyfifteen minutes. The solid which formed was collected by filtration,washed with water and dried at approximately 50° C. in vacuo to obtain21.4 g of 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoicacid (Formula II: Y═4--N(CH₃)₂ ; R═R¹ ═R² ═R³ ═CH₃), a palegreen-colored solid which melted over the range of 179° to 184° C. Afterone recrystallization from toluene, the melting point was 210° to 212°C.

EXAMPLE 3

A mixture of 38.0 ml of water, 17.4 g (0.1 mole) of 85.5 percent4-dimethylaminobenzaldehyde, 6.0 g (0.1 mole) of urea, 12.6 g (0.1 mole)of N,N-dimethylaniline, 18.2 g (0.11 mole) of 3-dimethylaminobenzoicacid and 14.6 ml (0.273 mole) of concentrated sulfuric acid wasmaintained at a temperature in the range of 90° to 95° C. forapproximately two and one-half hours with stirring. Slowly, 240.0 ml ofwater was added to the reaction mixture and the resulting mixture wasstirred for approximately eight hours. The mixture was filtered toremove the insolubles and the filtrate was added with stirring to asolution of 30.0 ml of concentrated ammonium hydroxide dissolved in150.0 ml of water. The pH of the resultant mixture was adjusted to 11.0by gradually adding 21.6 g of 90 percent potassium hydroxide. Afterstirring approximately one-half hour, the mixture was filtered retainingboth the filtercake and the filtrate. The filtrate was adjusted to a pHof approximately 4.8 by slowly adding glacial acetic acid. The solidwhich formed was collected by filtration, washed with water and dried invacuo to obtain 4.1 g of2-[bis(4-dimethylaminophenyl)]methyl-5-dimethylaminobenzoic acid(Formula II: Y═4--N(CH₃)₂ ; R═R¹ ═R² ═R³ ═CH₃), a solid.

The filtercake from the alkaline filtration above was extracted byresuspending it in a solution of 500.0 ml of water and 5.5 g of 90percent potassium hydroxide, maintaining the suspension at approximately50° C. for approximately thirty minutes and filtering the suspensionsaving both the filtercake and the filtrate. The filtrate was adjustedto a pH of approximately 4.8 by adding glacial acetic acid. The solidwhich formed was collected by filtration, washed with water and dried invacuo to obtain an additional 24.6 g of2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. Onegram of this product was recrystallized from toluene to obtain a paleyellow solid which melted over the range of 212° to 218° C. Thefiltercake obtained from the alkaline extraction above was extracted asecond time to obtain yet another 1.7 g of the desired product.

EXAMPLE 4

With stirring, a mixture of 15.3 g (0.1 mole) of 97.7 percent4-dimethylaminobenzaldehyde, 6.0 g (0.1 mole) of urea, 14.9 g (0.1 mole)of N,N-diethylaniline, 18.2 g (0.106 mole) of 3-dimethylaminobenzoicacid, 76.0 ml of water and 14.6 ml of concentrated sulfuric acid wasmaintained at a temperature in the range of 90° to 95° C. forapproximately four hours. Slowly, 200.0 ml of water was added and theresulting mixture was cooled to 30° C. The resulting mixture wasclarified by filtration to remove a trace of a dark orange solid. Thefiltrate was adjusted to pH 10.5 by the dropwise addition of a solutionconsisting of 43.0 g of 90 percent potassium hydroxide dissolved in200.0 ml of water resulting in an oily dark green-colored tar-likesubstance separating in the bottom of the mixture. The supernatantliquid was decanted from the tar-like material saving both the liquidand the tar-like substance. The decant was adjusted to pH 4.7 and asecond green tar formed. The supernatant liquid was decanted.Approximately two grams from each portion of the tar-like substanceswere mixed and dissolved in chloroform. The desired product was isolatedfrom the chloroform solution by column chromatography using a columnpacked with 40-140 mesh silica gel employing chloroform to elute thefirst two fractions through the column and acetone to elute the thirdand fourth fractions through the column. The desired product wasisolated from the third fraction by allowing the fraction to evaporateto dryness and then triturating the residue with hexane. The resultingsolid was collected by filtration and dried in vacuo to obtain 0.6 g of2-[(4-diethylaminophenyl)(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoicacid (Formula II: Y═4--N(CH₃)₂ ; R═R¹ ═CH₃ ; R² ═R³ ═C₂ H₅), a palegreen-gray-colored solid which melted at 78° to 83° C. The nuclearmagnetic resonance spectrum was consistent with the assigned structure.

EXAMPLE 5

A mixture of 15.3 g (0.1 mole) of 97.7 percent4-dimethylaminobenzaldehyde, 6.0 g (0.1 mole) of urea, 21.4 g (0.1 mole)of 98.8 percent N-benzyl-N-ethylaniline, 18.2 g (0.106) of 96.2 percent3-dimethylaminobenzoic acid, 24.0 ml of concentrated hydrochloric acidand 70.0 ml of water was maintained at a temperature in the range of 90°to 95° C. for approximately four and one-half hours. After cooling toroom temperature, a solution of 300.0 ml of water and 43.0 g of 90percent potassium hydroxide was added dropwise to the reaction mixture.While maintaining a temperature of less than 40° C., there was addedgradually 29.1 g (0.1 mole) of 93 percent potassium persulfate. Theresultant mixture was stirred for approximately sixteen hours. A bluetar-like material was collected by decanting the supernatant liquid andwas dried in a vacuum oven at approximately 66° C. to obtain 49.8 g ofblue tar which analyzed by ultraviolet spectroscopy was determined tocontain 25.7 g of3-(4-dimethylaminophenyl)-3-[4-(N-benzyl-N-ethyl)aminophenyl]-6-dimethylaminophthalide(Formula I: Y═4--N(CH₃)₂ ; R═R¹ ═CH₃ ; R² ═C₂ H₅ ; R³ ═CH₂ C₆ H₅).

EXAMPLE 6

A. With stirring, a mixture of 15.3 g (0.1 mole) of 97.7 percent4-dimethylaminobenzaldehyde, 6.0 g (0.1 mole) of urea, 21.4 g (0.1 mole)of 98.8 percent N-ethyl-N-benzylaniline, 18.2 g (0.106 mole) of 96.2percent 3-dimethylaminobenzoic acid, 76.0 ml of water and 14.6 ml ofconcentrated sulfuric acid was maintained at a temperature in the rangeof 90° to 95° C. for approximately four and one-half hours. Slowly,200.0 ml of water was added to the reaction mixture and the dilutedmixture was cooled to approximately 30° C. After clarification byfiltration to remove a trace of insolubles, the filtrate was adjusted topH 11.4 by the gradual addition of a solution consisting of 200.0 ml ofwater and 43.0 g of 90 percent potassium hydroxide. The pH of thesolution was adjusted to 4.6 by gradually adding glacial acetic acid.The solid which formed was collected by filtration and dried in vacuo toobtain 50.8 g of a soft, sticky blue product. The sticky product wasdissolved in dilute hydrochloric acid with heating. Gradually the pH wasadjusted to 3.5 with the addition of dilute sodium hydroxide. The solidwhich formed was collected by filtration and washed with water. Thefilter cake coalesced into a tar-like mass. The tar-like mass wasdissolved in a mixture of glacial acetic acid, water and hydrochloricacid. The pH of the solution was adjusted gradually by adding dilutesodium hydroxide while collecting four fractions, one each at pHs of2.6, 2.9, 3.6 and 4.6 by filtration of the solid which precipitated.Each of the fractions were analyzed by thin layer chromatography. Thefractions obtained at pH 3.6 and 4.6 contained predominantly the desired2-[(4-dimethylaminophenyl)(4-N-ethylbenzylaminophenyl)methyl]-5-dimethylaminobenzoicacid (Formula II: Y═4--N(CH₃)₂ ; R═R¹ ═CH₃ ; R² ═C₂ H₅ ; R³ ═CH₂ C₆ H₅).

B. The fraction isolated at pH 3.6 was suspended in water and thendissolved by adding dilute sodium hydroxide solution with gentleheating. Gradually, potassium persulfate was added to the solution untilno additional precipitate formed. The solid was collected by filtration,ashed with water and dried to obtain predominantly3-(4-dimethylaminophenyl)-3-[4-(N-ethylbenzylaminophenyl)]-6-dimethylphthalide(Formula I: Y═4--N(CH₃)₂ ; R═R¹ ═CH₃ ; R² ═C₂ H₅ ; R³ ═CH₂ C₆ H₅), ablue-colored solid. After recrystallization from toluene theblue-gray-colored solid had both an infrared spectrum and a nuclearmagnetic resonance spectrum concordant with the assigned structure.

It is contemplated that by following procedures similar to thosedescribed in the foregoing examples but interacting the appropriateY-benzaldehyde, the appropriate 4-N-R² -N-R³ -aniline and theappropriate 3-N-R-N-R¹ -aminobenzoic acid, in the acidic medium shown inColumn 5 hereinbelow there will be obtained the 2-[(Y-phenyl)(4-N-R²-N-R³ -aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acids of Formula IIdescribed in Column 6 hereinbelow and that said benzoic acids of Column6 can be oxidized with the oxidizing agents shown in Column 7hereinbelow to obtain the 3-(Y-phenyl)-3-(4-N-R² -N-R³-aminophenyl)-6-N-R-N-R¹ -aminophthalides of Formula I, Examples 7-20,presented in Table A hereinbelow.

                                      TABLE A                                     __________________________________________________________________________    PART I                                                                        Example                        3-N--R--N--R.sup.1 --                                                                     Acidic                             No.  Y-Benzaldehyde                                                                           N--R.sup.2 --N--R.sup.3 --Aniline                                                            Aminobenzoic Acid                                                                         Medium                             __________________________________________________________________________     7   Benzaldehyde                                                                             N,N--Di- -n-butylaniline                                                                     3-Diethylamino-                                                                           Methane-                                                          benzoic acid                                                                              sulfonic                                                                      acid                                8   2-Methylbenz-                                                                            N,N--Di-isopropylaniline                                                                     3-N--Ethyl-N--methyl-                                                                     Chloro-                                 aldehyde                  aminobenzoic acid                                                                         acetic                                                                        acid                                9   2-Chlorobenz-                                                                            N--Benzyl-N--ethyl-                                                                          3-Di- -n-propylamino-                                                                     Phosphoric                              aldehyde   aniline        benzoic acid                                                                              acid                               10   3-Methoxybenz-                                                                           N,N--sec-Butylaniline                                                                        3-N--Ethylbenzyl-                                                                         Methane-                                aldehyde                  aminobenzoic acid                                                                         sulfonic                                                                      acid                               11   4-Methoxybenz-                                                                           N--Ethyl-N--methyl-                                                                          3-Methylamino-                                                                            Acetic                                  aldehyde   aniline        benzoic acid                                                                              acid                               12   4-Ethoxybenz-                                                                            N,N--Di- -n-Propyl-                                                                          3-Dibenzylamino-                                                                          Dichloro-                               aldehyde   aniline        benzoic acid                                                                              acetic                                                                        acid                               13   4-Diethylamino-                                                                          N--(4-Chlorobenzyl)-                                                                         3-Diethylamino-                                                                           Trichloro-                              benzaldehyde                                                                             N--methylaniline                                                                             benzoic acid                                                                              acetic                                                                        acid                               14   4-Di-isopropylamino-                                                                     N--n-Propyl-N--benzyl-                                                                       3-[N--(4-Chlorobenzyl)-                                                                   Acetic                                  benzaldehyde                                                                             aniline        N-- -n-butylamino]-                                                                       acid                                                              benzoic acid                                   15   4-Benzylamino-                                                                           N,N--Dibenzylaniline                                                                         3-Di- - n-propylamino-                                                                    Chloro-                                 benzaldehyde              benzoic acid                                                                              acetic                                                                        acid                               16   4-N--Ethylbenzyl-                                                                        N--Phenyl-N--methylaniline                                                                   3-Diethylamino-                                                                           Methane-                                aminobenzaldehyde         benzoic acid                                                                              sulfonic                                                                      acid                               17   4-Dibenzylamino-                                                                         N--(4-Methylbenzyl)-N--                                                                      3-Aminobenzoic                                                                            Dichloro-                               benzaldehyde                                                                             methylaniline  acid        acetic                                                                        acid                               18   4-Di-sec-butylamino-                                                                     N--(2,4-Dichlorobenzyl)-N--                                                                  3-Methylamino-                                                                            Trichloro-                              benzaldehyde                                                                             methylaniline  benzoic acid                                                                              acetic                                                                        acid                               19   4-Di- -n-propylamino-                                                                    N--(4-Methylphenyl)-N--                                                                      3-Benzylamino-                                                                            Phosphoric                              benzaldehyde                                                                             ethylaniline   benzoic acid                                                                              acid                               20   4-Isopropylbenz-                                                                         N--Benzyl-N-- -n-propyl-                                                                     3-Diethylamino-                                                                           Methane-                                aldehyde   aniline        benzoic acid                                                                              sulfonic                                                                      acid                               __________________________________________________________________________    PART II                                                                       Example                 Oxidizing                                             No.  Benzoic Acid of Formula II                                                                       Agent  Phthalide of Formula I                         __________________________________________________________________________     7   2-[Phenyl(4-di- -n-butyl-                                                                        Hydrogen                                                                             3-Phenyl-3-(4-di- -n-butylamino-                    aminophenyl)methyl]-5-diethyl-                                                                   peroxide                                                                             phenyl)-6-diethylaminophthalide                     aminobenzoic acid                                                         8   2-[(2-Methylphenyl)(4-di-iso-                                                                    Oxygen 3-(2-Methylphenyl)-3-(4-di-iso-                     propylaminophenyl)methyl]-5-(N--                                                                        propylaminophenyl)-6-(N--ethyl-                     ethyl-N--methyl)aminobenzoic acid                                                                       N--methyl)aminophthalide                        9   2-[(2-Chlorophenyl)(4-N--                                                                        Potassium                                                                            3-(2-Chlorophenyl)-3-(4-N--                         ethylbenzylaminophenyl)methyl]-5-                                                                permaganate                                                                          ethylbenzylaminophenyl)-6-di- -n-                   di- -n-propylaminobenzoic acid                                                                          propylaminophthalide                           10   2-[(3-Methoxyphenyl)(4-di-sec-                                                                   Air    3-(3-Methoxyphenyl)-3-(4-di-sec-                    butylaminophenyl)methyl]-5-(N--                                                                         butylaminophenyl)-6-N--ethylbenz-                   ethylbenzylamino)benzoic acid                                                                           ylaminophthalide                               11   2-[(4-Methoxyphenyl)(4-N--                                                                       Hydrogen                                                                             3-(4-Methoxyphenyl)-3-(4-N--                        ethyl-N--methylaminophenyl)methyl]-                                                              peroxide                                                                             ethyl-N--methylaminophenyl)-6-                      5-methylaminobenzoic acid methylaminophthalide                           12   2-[(4-Ethoxyphenyl)(4-di- -n-                                                                    Oxygen 3-(4-Ethoxyphenyl)-3-(4-di- -n-                     propylaminophenyl)methyl]-5-dibenz-                                                                     propylaminophenyl)-6-dibenzyl-                      ylaminobenzoic acid       aminophthalide                                 13   2-{(4-Diethylaminophenyl)[(4-                                                                    Potassium                                                                            3-(4-Diethylaminophenyl)-3-[4-N--                   N--(4-chlorobenzyl)-N--methylamino-                                                              permaganate                                                                          (4-chlorobenzyl)-N--methylamino-                    phenyl]methyl}-5-diethylaminobenzoic                                                                    phenyl]-6-diethylaminophthalide                     acid                                                                     __________________________________________________________________________    Example                 Oxidizing                                             No.  Benzoic Acid of Formula V                                                                        Agent  Phthalide of Formula I                         __________________________________________________________________________    14   2-[(4-Di-isopropylaminophenyl)                                                                   Air    3-(4-Di-isopropylaminophenyl)-                      (4-N--propylbenzylamino)methyl]-                                                                        3-(4-N--propylbenzylamino)-6-[N--                   5-[N-(4-chlorobenzyl)-N--butyl-                                                                         (4-chlorobenzyl)-N--butylamino-                     amino]benzoic acid        phthalide                                      15   2-[(4-Benzylaminophenyl)(4-                                                                      Potassium                                                                            3-(4-Benzylaminophenyl)-3-(4-                       dibenzylaminophenyl)methyl]-5-                                                                   persulfate                                                                           dibenzylaminophenyl)-6-di- -n-                      di- -n-propylaminobenzoic acid                                                                          propylaminophthalide                           16   2-[(4-N--Ethylbenzylaminophenyl)                                                                 Hydrogen                                                                             3-(4-N--Ethylbenzylaminophenyl)-                    (4-N--methyl-N--phenylamino)methyl]-                                                                    3-(4-N--methyl-N--phenylaminon-                     5-diethylaminobenzoic acid                                                                              phenyl-6-diethylaminophthalide                 17   2-{(4-Dibenzylaminophenyl)[4-                                                                    Oxygen 3-(4-Dibenzylaminophenyl)-3-[4-                     N--(4-methylbenzyl)-N--methylamino-                                                                     N--(4-methylbenzyl)-N--methyl-                      phenyl]methyl}-5-aminobenzoic acid                                                                      aminophenyl]-6-aminophthalide                  18   2-{(4-Di-sec-butylaminophenyl)                                                                   Air    3-(4-Di-sec-butylaminophenyl)-                      [4-N--(2,4-dichlorobenzyl)-N--methyl-                                                                   3-[4-N--(2,4-dichlorobenzyl)-N--                    aminophenyl]methyl}-5-methylamino-                                                                      methylaminophenyl]-6-methyl-                        benzoic acid              aminophthalide                                 19   2-{(4-Di- -n-propylaminophenyl)                                                                  Hydrogen                                                                             3-(4-Di- -n-propylaminophenyl)-3-                   [4-N--(4-methylphenyl)-N--ethylamino-                                                            peroxide                                                                             [4-N--(4-methylphenyl)-N--ethyl-                    phenyl]methyl}-5-benzylaminobenzoic                                                                     aminophenyl]-6-benzylamino-                         acid                      phthalide                                      20   2-[(4-Isopropylphenyl)(4-N-- -n-                                                                 Potassium                                                                            3-(4-Isopropylphenyl)-3-(4-N-- -n-                  propylbenzylaminophenyl)methyl]-5-                                                               persulfate                                                                           propylbenzylaminophenyl)-6-di-                      diethylaminobenzoic acid  ethylaminophthalide                            __________________________________________________________________________

What is claimed is:
 1. A process for the production of2-[(Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoicacids of the formula ##STR4## wherein: R, R¹, R² and R³ may be identicalor different and each represents hydrogen, non-tertiary alkyl of one tofour carbon atoms, hydroxyalkyl of two or three carbon atoms, phenyl orbenzyl or phenyl or benzyl substituted in the benzene ring by one or twoof halo or alkyl of one to three carbon atoms; andY represents hydrogen,halo, non-tertiary alkyl of one to four carbon atoms, non-tertiaryalkoxy of one to four carbon atoms, or dialkylamino orN-alkylbenzylamino in which alkyl is non-tertiary alkyl of one to fourcarbon atoms and benzyl may be substituted in the benzene ring by one ortwo of halo or alkyl of one to three carbon atomswhich comprisesreacting in approximately equimolecular proportions a Y-benzaldehyde, anN-R² -N-R³ -aniline and a 3-N-R-N-R¹ -aminobenzoic acid in which R, R¹,R², R³ and Y have the meanings given for Formula II, in an acidicmedium.
 2. A process according to claim 1 for preparing a2-[(4-Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹-aminobenzoic acid.
 3. A process according to claim 2 for preparing a2-[(4-Y-phenyl)(4-N-R² -N-R³ -aminophenyl)methyl]-5-N-R-N-R¹-aminobenzoic acid wherein Y is a dialkylamino or N-alkylbenzylamino inwhich alkyl is a non-tertiary alkyl of one to four carbon atoms.
 4. Aprocess according to claim 3 for preparing a 2-[(4-Y-phenyl)(4-N-R²-N-R³ -aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acid wherein R, R¹,R² and R³ are nontertiary alkyl of one to four carbon atoms or benzyl.5. A process according to claim 1 for preparing a 2-[(4-Y-phenyl)(4-N-R²-N-R³ -aminophenyl)methyl]-5-N-R-N-R¹ -aminobenzoic acid wherein theacidic medium is selected from the group consisting of aqueous sulfuricacid, hydrochloric acid and methanesulfonic acid.